Cytomegalovirus (CMV) infects half of the US population, establishing a lifetime persistent infection. One percent of infants are born with CMV infection and a subset of these infants suffers permanent developmental disabilities. CMV is life-threatening for individuals with a compromised immune system, including solid organ and stem cell transplant patients. Additionally, infection or reactivation of CMV resulting in viremia in solid organ transplant patients has been correlated with chronic graft rejection. Through constant surveillance, natural killer (NK) and T cells cooperatively control CMV throughout an individual?s life. We have recently identified a subpopulation of NK cells and T cells bearing the activating CD94-NKG2C receptor that preferentially respond to acute CMV infection in both solid organ transplant recipients and hematopoietic stem cell transplantation recipients. These CD94-NKG2C+ NK cells are specific for CMV, in that they do not respond to acute infection with Epstein-Barr virus during infectious mononucleosis or Herpes Simplex Virus, and these NK cells have only been observed to be re-activated in individuals who have been infected with CMV. Within this CMV-specific CD94-NKG2C+ NK cell population we have identified a unique subset of NK cells that do not express the FcepsilonRIepisilon signaling subunit, which is expressed on all nave NK cells in humans, and these NK cells possess enhanced antibody-dependent cellular cytotoxicity function. The overall goal of this project is to determine how a specific subset of human NK cells and T cells expressing NK receptors respond to CMV infection or reactivation in solid organ transplant recipients and whether the frequency of these cells or their kinetic response to infection contributes to host protection against acute CMV infection or influences graft survival. We will use state-of-the-art CyTOF mass cytometry and functional assays to evaluate the kinetics of the NK cell response in kidney transplant patients who control or fail to control infection or reactivation of CMV. These studies in Project 2 will complement studies of T cells in Project 1 and B cells in Project 3 to define the dynamic interactions and cross-regulation between the innate and adaptive immune response against CMV.